Correlates of protection against COVID-19 infection and intensity of symptomatic disease in vaccinated individuals exposed to SARS-CoV-2 in households in Israel (ICoFS): a prospective cohort study.

BACKGROUND: Identifying COVID-19 correlates of protection and immunity thresholds is important for policy makers and vaccine development. We aimed to identify correlates of protection of BNT162b2 (Pfizer-BioNTech) vaccination against COVID-19. METHODS: In this prospective cohort study, households within a radius of 40 km of the Sheba Medical Center in Israel in which a new SARS-CoV-2 infection (defined as the index case) was detected within the previous 24 h were approached between July 25 and Nov 15, 2021. We included adults (aged >18 years) who had received one or two vaccine doses, had an initial negative SARS-CoV-2 PCR and no previous infection reported, and had a valid IgG and neutralising antibody result. The exposure of interest was baseline immune status, including IgG antibody concentration, neutralising antibody titre, and T-cell activation. The outcomes of interest were PCR-positive SARS-CoV-2 infection between day 2 and day 21 of follow-up and intensity of disease symptoms (self-reported via a telephone questionnaire) among participants who had a confirmed infection. Multivariable logistic and ordered logit ordinal regressions were used for the adjusted analysis. To identify immunological thresholds for clinical protection, we estimated the conditional probability of infection and moderate or severe disease for individuals with pre-exposure IgG and neutralising antibody concentrations above each value observed in the study data. FINDINGS: From 16 675 detected index cases in the study region, 5718 household members agreed to participate, 1461 of whom were eligible to be included in our study. 333 (22·8%) of 1461 household members who were not infected with SARS-CoV-2 at baseline were infected within 21 days of follow-up. The baseline (pre-exposure) IgG and neutralising antibodies were higher in participants who remained uninfected than in those who became infected (geometric mean IgG antibody concentration 168·2 binding antibody units [BAU] per mL [95% CI 158·3-178·7] vs 130·5 BAU/mL [118·3-143·8] and geometric mean neutralising antibody titre 197·5 [181·9-214·4] vs 136 ·7 [120·3-155·4]). Increasing IgG and neutralising antibody concentrations were also significantly associated with a reduced probability of increasing disease severity. Odds of infection were significantly reduced each time baseline IgG antibody concentration increased by a factor of ten (odds ratio [OR] 0·43 [95% CI 0·26-0·70]) and each time baseline neutralising antibody titre increased by a factor of two (0·82 [0·74-0·92]). In our cohort, the probability of infection if IgG antibody concentrations were higher than 500 BAU/mL was 11% and the probability of moderate disease severity was 1%; the probability of infection if neutralising antibody titres were above or equal to 1024 was 8% and the probability of moderate disease severity was 2%. T-cell activation rates were not significantly associated with reduced probability of infection (OR 1·04, 95% CI 0·83-1·30). INTERPRETATION: Both IgG and neutralising antibodies are correlates of protection against SARS-CoV-2 infection. Our data suggest that IgG concentrations higher than 500 BAU/mL and neutralising antibody titres of 1024 or more are thresholds for immunological protection from SARS-CoV-2 delta variant infection. Potentially, updated protective thresholds against emerging variants of concern could be calculated, which could support decision makers on administration of new vaccination strategies and on the optimal period between vaccine doses. FUNDING: Israeli Ministry of Health.

Overcoming the effect of pandemic fatigue on vaccine hesitancy-Will belief in science triumph?

PURPOSE: The study aims to examine the factors that impact vaccination uptake and additional protective behavior during the fourth wave of the pandemic in Israel, whereas the "pandemic fatigue" phenomenon has been identified as a hurdle to adherence to protective health behaviors against coronavirus disease 2019 (COVID-19). DESIGN: A cross-sectional, structured questionnaire was utilized for this investigation in September 2021, during the fourth wave of the pandemic. METHODS: A sample of the adult (18+) Israeli population was employed for the study. Recruiting participants for the study was conducted through an online internet panel company that consists of over 100,000 members, representing all geographic and demographic sectors of the Israeli population. RESULTS: Our findings indicate that pandemic fatigue has begun to have cascading effects on vaccination efforts. In particular, this study found that at this stage of the COVID-19 pandemic, trust in authorities, and even threat perception components, such as concern and fear of contracting the disease, are incapable of predicting vaccination uptake. Instead, perception of the importance of the vaccine and its effectiveness are predictive of vaccination uptake. CONCLUSION: The findings indicate that at this stage of the pandemic, focusing on the robustness of the science behind the vaccine is more important than trying to regain public trust. The findings also suggest that risk communication employing fear tactics is losing its capacity to generate motivation for vaccination. CLINICAL RELEVANCE: The findings of this study reveal lessons learned from the COVID-19 global pandemic. Specifically, the study reveals how in times of prolonged crisis, we can currently and, in the future, prepare improved strategies for public communication in order to promote uptake of protective health behavior, such as vaccination.

Similarity of Protection Conferred by Previous SARS-CoV-2 Infection and by BNT162b2 Vaccine: A 3-Month Nationwide Experience From Israel.

The worldwide shortage of vaccination against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection while the pandemic still remains uncontrolled has led many countries to the dilemma of whether or not to vaccinate previously infected persons. Understanding the level of protection conferred by previous infection compared with that of vaccination is important for policy-making. We analyzed an updated individual-level database of the entire population of Israel to assess the protection provided by both prior infection and vaccination in preventing subsequent SARS-CoV-2 infection, hospitalization with coronavirus disease 2019 (COVID-19), severe disease, and death due to COVID-19. Outcome data were collected from December 20, 2020, to March 20, 2021. Vaccination was highly protective, with overall estimated effectiveness of 94.5% (95% confidence interval (CI): 94.3, 94.7) for documented infection, 95.8% (95% CI: 95.2, 96.2) for hospitalization, 96.3% (95% CI: 95.7, 96.9) for severe illness, and 96.0% (95% CI: 94.9, 96.9) for death. Similarly, the overall estimated level of protection provided by prior SARS-CoV-2 infection was 94.8% (95% CI: 94.4, 95.1) for documented infection, 94.1% (95% CI: 91.9, 95.7) for hospitalization, and 96.4% (95% CI: 92.5, 98.3) for severe illness. Our results should be considered by policy-makers when deciding whether or not to prioritize vaccination of previously infected adults.

Fighting a pandemic: sociodemographic disparities and coronavirus disease-2019 vaccination gaps-a population study.

BACKGROUND: Data suggest lower coronavirus disease-2019 (COVID-19) vaccination coverage among minority and disadvantaged groups. We aimed to identify interactions between sociodemographic factors associated with vaccination gaps. METHODS: This population study used Israeli National COVID-19 data (extracted: 10 May 2021). The analysis comprised 6 478 999 individuals age ≥15 years with aggregated area-level data on sex and age distribution and no COVID-19 history. We estimated vaccination hazard and cumulative incidence using the Fine and Gray competing risk model. RESULTS: Older age and higher socioeconomic status (SES) were associated, with stepwise higher cumulative vaccination rates (age 20-24: 67%, age ≥ 75: 96%; SES 1-3: 61%, 4-5: 74.2%, 6-7: 82%, 8-10: 87%). We found the lowest vaccination rates in Arab (65%) and Ultra-Orthodox Jewish (54%) areas. SES modified the association in Arab neighbourhoods, with higher coverage than in the non-Orthodox Jewish reference group in SES 1-3 [adjusted hazard ratio (HR) = 1.06; 95% confidence interval (CI): 1.02-1.11], and gradually lower coverage in higher SES classes (SES 6-7: HR = 0.83; 95% CI: 0.79-0.87). Vaccination rates were also higher among younger Arabs (≤45 years) compared with age counterparts in the reference population group (age 25-34: HR = 1.18; 95% CI: 1.12-1.28) and lower than the reference group among Arabs age ≥45 years. Among Ultra-Orthodox Jews, vaccination HRs remained below one across age and SES classes. CONCLUSIONS: Age and SES modified the association between population group and vaccination coverage. Identifying the interplay between sociodemographic characteristics and the underlying explanations may improve targeted efforts, aimed at closing vaccination coverage gaps and mitigating COVID-19.

BNT162b2 COVID-19 vaccine and correlates of humoral immune responses and dynamics: a prospective, single-centre, longitudinal cohort study in health-care workers.

BACKGROUND: Concurrent with the Pfizer-BioNTech BNT162b2 COVID-19 vaccine roll-out in Israel initiated on Dec 19, 2020, we assessed the early antibody responses and antibody kinetics after each vaccine dose in health-care workers of different ages and sexes, and with different comorbidities. METHODS: We did a prospective, single-centre, longitudinal cohort study at the Sheba Medical Centre (Tel-Hashomer, Israel). Eligible participants were health-care workers at the centre who had a negative anti-SARS-CoV-2 IgG assay before receiving the first dose of the intramuscular vaccine, and at least one serological antibody test after the first dose of the vaccine. Health-care workers with a positive SARS-CoV-2 PCR test before vaccination, a positive anti-SARS-CoV-2 IgG serology test before vaccination, or infection with COVID-19 after vaccination were excluded from the study. Participants were followed up weekly for 5 weeks after the first vaccine dose; a second dose was given at week 3. Serum samples were obtained at baseline and at each weekly follow-up, and antibodies were tested at 1-2 weeks after the first vaccine dose, at week 3 with the administration of the second vaccine dose, and at weeks 4-5 (ie, 1-2 weeks after the second vaccine dose). Participants with comorbidities were approached to participate in an enriched comorbidities subgroup, and at least two neutralising assays were done during the 5 weeks of follow-up in those individuals. IgG assays were done for the entire study population, whereas IgM, IgA, and neutralising antibody assays were done only in the enriched comorbidities subgroup. Concentrations of IgG greater than 0·62 sample-to-cutoff (s/co) ratio and of IgA greater than 1·1 s/co, and titres of neutralising antibodies greater than 10 were considered positive. Scatter plot and correlation analyses, logistic and linear regression analyses, and linear mixed models were used to investigate the longitudinal antibody responses. FINDINGS: Between Dec 19, 2020, and Jan 30, 2021, we obtained 4026 serum samples from 2607 eligible, vaccinated participants. 342 individuals were included in the enriched comorbidities subgroup. The first vaccine dose elicited positive IgG and neutralising antibody responses at week 3 in 707 (88·0%) of 803 individuals, and 264 (71·0%) of 372 individuals, respectively, which were rapidly increased at week 4 (ie, 1 week after the second vaccine dose) in 1011 (98·4%) of 1027 and 357 (96·5%) of 370 individuals, respectively. Over 4 weeks of follow-up after vaccination, a high correlation (r=0·92) was detected between IgG against the receptor-binding domain and neutralising antibody titres. First-dose induced IgG response was significantly lower in individuals aged 66 years and older (ratio of means 0·25, 95% CI 0·19-0·31) and immunosuppressed individuals (0·21, 0·14-0·31) compared with individuals aged 18·00-45·99 years and individuals with no immunosuppression, respectively. This disparity was partly abrogated following the second dose. Overall, endpoint regression analysis showed that lower antibody concentrations were consistently associated with male sex (ratio of means 0·84, 95% CI 0·80-0·89), older age (ie, ≥66 years; 0·64, 0·58-0·71), immunosuppression (0·44, 0·33-0·58), and other specific comorbidities: diabetes (0·88, 0·79-0·98), hypertension (0·90, 0·82-0·98), heart disease (0·86, 0·75-1·00), and autoimmune diseases (0·82, 0·73-0·92). INTERPRETATION: BNT162b2 vaccine induces a robust and rapid antibody response. The significant correlation between receptor-binding domain IgG antibodies and neutralisation titres suggests that IgG antibodies might serve as a correlate of neutralisation. The second vaccine dose is particularly important for older and immunosuppressed individuals, highlighting the need for timely second vaccinations and potentially a revaluation of the long gap between doses in some countries. Antibody responses were reduced in susceptible populations and therefore they might be more prone to breakthrough infections. FUNDING: Sheba Medical Center, Israel Ministry of Health.

Developing a National Set of Health Equity Indicators Using a Consensus Building Process.

BACKGROUND: Considerable health inequities documented in Israel between communities, populations and regions, undermine the rights of all citizens to optimal health. The first step towards health equity is agreement on a set of national indicators, reflecting equity in healthcare provision and health outcomes, and allowing monitoring of the impact of interventions on the reduction of disparities. We describe the process of reaching a consensus on a defined set of national equity indicators. METHODS: The study was conducted between January 2019 and June 2020, in a multistage design: (A) Identifying appropriate and available inequity measures via interviews with stakeholders. (B) Agreement on the screening criteria (public health importance; gap characteristics; potential for change; public interest) and relative weighting. (C) Constructing the consultation framework as an online, 3-round Delphi technique, with a range of experts recruited from the health, welfare and education sectors. RESULTS: Participants were of diverse age, gender, geographic location, religion and ethnicity, and came from academia, healthcare provision, government ministries and patient representative groups. Thirty measures of inequity, presented to participants, represented the following domains: Health promotion (11 indicators), acute and chronic morbidity (11), life expectancy and mortality (2), health infrastructures and affordability of care (4), education and employment (2). Of the 77 individuals contacted, 75 (97%) expressed willingness to participate, and 55 (73%) completed all three scoring rounds. The leading ten indicators were: Diabetes care, childhood obesity, adult obesity, distribution of healthcare personnel, fatal childhood injuries, cigarette smoking, infant mortality, ability to afford care, access to psychotherapy and distribution of hospital beds. Agreement among raters, measured as intra-class correlation coefficient (ICC), was 0.75. CONCLUSION: A diverse range of consultants reached a consensus on the most important national equity indicators, including both clinical and system indicators. Results should be used to guide governmental decision-making and inter-sectoral strategies, furthering the pursuit of a more equitable healthcare system.

Waning Immune Humoral Response to BNT162b2 Covid-19 Vaccine over 6 Months.

BACKGROUND: Despite high vaccine coverage and effectiveness, the incidence of symptomatic infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been increasing in Israel. Whether the increasing incidence of infection is due to waning immunity after the receipt of two doses of the BNT162b2 vaccine is unclear. METHODS: We conducted a 6-month longitudinal prospective study involving vaccinated health care workers who were tested monthly for the presence of anti-spike IgG and neutralizing antibodies. Linear mixed models were used to assess the dynamics of antibody levels and to determine predictors of antibody levels at 6 months. RESULTS: The study included 4868 participants, with 3808 being included in the linear mixed-model analyses. The level of IgG antibodies decreased at a consistent rate, whereas the neutralizing antibody level decreased rapidly for the first 3 months with a relatively slow decrease thereafter. Although IgG antibody levels were highly correlated with neutralizing antibody titers (Spearman's rank correlation between 0.68 and 0.75), the regression relationship between the IgG and neutralizing antibody levels depended on the time since receipt of the second vaccine dose. Six months after receipt of the second dose, neutralizing antibody titers were substantially lower among men than among women (ratio of means, 0.64; 95% confidence interval [CI], 0.55 to 0.75), lower among persons 65 years of age or older than among those 18 to less than 45 years of age (ratio of means, 0.58; 95% CI, 0.48 to 0.70), and lower among participants with immunosuppression than among those without immunosuppression (ratio of means, 0.30; 95% CI, 0.20 to 0.46). CONCLUSIONS: Six months after receipt of the second dose of the BNT162b2 vaccine, humoral response was substantially decreased, especially among men, among persons 65 years of age or older, and among persons with immunosuppression.

Decreased infectivity following BNT162b2 vaccination: A prospective cohort study in Israel.

BACKGROUND: BNT162b2 was shown to be 92% effective in preventing COVID-19. Prioritizing vaccine rollout, and achievement of herd immunity depend on SARS-CoV-2 transmission reduction. The vaccine's effect on infectivity is thus a critical priority. METHODS: Among all 9650 HCW of a large tertiary medical center in Israel, we calculated the prevalence of positive SARS-CoV-2 qRT-PCR cases with asymptomatic presentation, tested following known or presumed exposure and the infectious subset (N-gene-Ct-value<30) of these. Additionally, infection incidence rates were calculated for symptomatic cases and infectious (Ct<30) cases. Vaccine effectiveness within three months of vaccine rollout was measured as one minus the relative risk or rate ratio, respectively. To further assess infectiousness, we compared the mean Ct-value and the proportion of infections with a positive SARS-CoV-2 antigen test of vaccinated vs. unvaccinated. The correlation between IgG levels within the week before detection and Ct level was assessed. FINDINGS: Reduced prevalence among fully vaccinated HCW was observed for (i) infections detected due to exposure, with asymptomatic presentation (VE(i)=65.1%, 95%CI 45-79%), (ii) the presumed infectious (Ct<30) subset of these (VE(ii)=69.6%, 95%CI 43-84%) (iii) never-symptomatic infections (VE(iii)=72.3%, 95%CI 48-86%), and (iv) the presumed infectious (Ct<30) subset (VE(iv)=83.0%, 95%CI 51-94%).Incidence of (v) symptomatic and (vi) symptomatic-infectious cases was significantly lower among fully vaccinated vs. unvaccinated individuals (VE(v)= 89.7%, 95%CI 84-94%, VE(vi)=88.1%, 95%CI 80-95%).The mean Ct-value was significantly higher in vaccinated vs. unvaccinated (27.3±1.2 vs. 22.2±1.0, p<0.001) and the proportion of positive SARS-CoV-2 antigen tests was also significantly lower among vaccinated vs. unvaccinated PCR-positive HCW (80% vs. 31%, p<0.001). Lower infectivity was correlated with higher IgG concentrations (R=0.36, p=0.01). INTERPRETATION: These results suggest that BNT162b2 is moderately to highly effective in reducing infectivity, via preventing infection and through reducing viral shedding. FUNDING: Sheba Medical Center, Israel.

The role of children in the spread of COVID-19: Using household data from Bnei Brak, Israel, to estimate the relative susceptibility and infectivity of children.

One of the significant unanswered questions about COVID-19 epidemiology relates to the role of children in transmission. This study uses data on infections within households in order to estimate the susceptibility and infectivity of children compared to those of adults. The data were collected from households in the city of Bnei Brak, Israel, in which all household members were tested for COVID-19 using PCR (637 households, average household size of 5.3). In addition, serological tests were performed on a subset of the individuals in the study. Inspection of the PCR data shows that children are less likely to be tested positive compared to adults (25% of children positive over all households, 44% of adults positive over all households, excluding index cases), and the chance of being positive increases with age. Analysis of joint PCR/serological data shows that there is under-detection of infections in the PCR testing, which is more substantial in children. However, the differences in detection rates are not sufficient to account for the differences in PCR positive rates in the two age groups. To estimate relative transmission parameters, we employ a discrete stochastic model of the spread of infection within a household, allowing for susceptibility and infectivity parameters to differ among children and adults. The model is fitted to the household data using a simulated maximum likelihood approach. To adjust parameter estimates for under-detection of infections in the PCR results, we employ a multiple imputation procedure using estimates of under-detection in children and adults, based on the available serological data. We estimate that the susceptibility of children (under 20 years old) is 43% (95% CI: [31%, 55%]) of the susceptibility of adults. The infectivity of children was estimated to be 63% (95% CI: [37%, 88%]) relative to that of adults.

Development and validation of a machine learning model predicting illness trajectory and hospital utilization of COVID-19 patients: A nationwide study.

OBJECTIVE: The spread of coronavirus disease 2019 (COVID-19) has led to severe strain on hospital capacity in many countries. We aim to develop a model helping planners assess expected COVID-19 hospital resource utilization based on individual patient characteristics. MATERIALS AND METHODS: We develop a model of patient clinical course based on an advanced multistate survival model. The model predicts the patient's disease course in terms of clinical states-critical, severe, or moderate. The model also predicts hospital utilization on the level of entire hospitals or healthcare systems. We cross-validated the model using a nationwide registry following the day-by-day clinical status of all hospitalized COVID-19 patients in Israel from March 1 to May 2, 2020 (n = 2703). RESULTS: Per-day mean absolute errors for predicted total and critical care hospital bed utilization were 4.72 ± 1.07 and 1.68 ± 0.40, respectively, over cohorts of 330 hospitalized patients; areas under the curve for prediction of critical illness and in-hospital mortality were 0.88 ± 0.04 and 0.96 ± 0.04, respectively. We further present the impact of patient influx scenarios on day-by-day healthcare system utilization. We provide an accompanying R software package. DISCUSSION: The proposed model accurately predicts total and critical care hospital utilization. The model enables evaluating impacts of patient influx scenarios on utilization, accounting for the state of currently hospitalized patients and characteristics of incoming patients. We show that accurate hospital load predictions were possible using only a patient's age, sex, and day-by-day clinical state (critical, severe, or moderate). CONCLUSIONS: The multistate model we develop is a powerful tool for predicting individual-level patient outcomes and hospital-level utilization.